Project Summary: Nutrients affect tissue stem cell lineages in all organisms. Interorgan signaling allows the impact of diet or physiological factors on one organ to be communicated to stem cell lineages elsewhere. Circulating levels of most energy substrates and metabolites vary with diet, and many of these activate G protein coupled receptors (GPCRs), which are associated with metabolic diseases, cancers and other disorders. It is therefore essential to investigate how GPCR signaling links metabolism to stem lineage processes in vivo. Adipocytes have key metabolic roles, and obesity increases the risk for many diseases. Among them are cancers, which share similarities with stem cells. Signaling pathways that control normal stem cells are often deregulated in cancers (e.g. diet-dependent pathways), and cancers and stem cells have large proliferative potential and generate differentiated cells in deregulated or controlled ways, respectively. The goal of this proposal is to study how diet controls adipocyte metabolism and how GPCR signaling mediates its effects on stem cell lineages using the Drosophila germline stem cell (GSC) model. Drosophila has highly conserved adipocyte metabolism and well characterized stem cells. One can readily identify GSCs and quantify self-renewal, proliferation, differentiation and survival along their lineage. GSCs and their progeny divide and grow faster on a rich diet, partially via insulin, steroid hormone, and Target of Rapamycin (TOR) signaling in the ovary. Adipocytes contribute to the GSC response to diet, as adipocyte-specific disruption of amino acid transport or TOR causes distinct GSC lineage phenotypes. Our unpublished data show that diet also regulates metabolic pathways in adipocytes, and key adipocyte enzymes influence GSC number, proliferation, and differentiation, survival of their daughters. In addition, our results show that distinct G proteins regulate GSC fate and division, and progeny survival, suggesting that GPCR signaling actively modulates the GSC lineage. We will test our hypothesis that key diet-dependent metabolic pathways in adipocytes control the levels of metabolites (or other downstream factors) that act directly on the ovary (or indirectly, through intermediate organs) to modulate the GSC lineage through the following aims: 1) To determine how macronutrients and diet-dependent hormones impact key adipocyte metabolic pathways; and 2) To probe the role of G protein coupled receptor (GPCR) signaling in the GSC lineage. Relevance: Obesity is prevalent in the western world and results in the abnormal function of fat cells, which in turn increases the risk for many diseases, including cancers. We propose to take advantage of powerful research tools in fruitflies to investigate how metabolic processes in fat cells normally generate signals that affect the function of stem cells in other parts of the body. Because of the high degree of evolutionary conservation of molecules and biological processes between fruitflies and humans, this work will likely provide valuable insights into diseases resulting from metabolic abnormalities in fat cells.